Aiming to decipher the biomarkers of response to neoadjuvant nivolumab treatment in patients with high-risk resectable HNSCC, Liu and Knochelmann et al. analyzed longitudinal tumor and blood samples from 12 individuals showing 33% responsiveness. In pretreatment tumor samples, high TMB was associated with improved RFS (but not OS) and PTEN signature enrichment and FLT4 mutations correlated with response. Mutations in CDKN2A; gain in YAP1, MDM2, and PPARG; and a high ratio of Tregs to Th17 cells correlated with resistance. Post-therapy, T cell clonal diversification and intratumoral T cell clonal expansion correlated with response.
Contributed by Shishir Pant
ABSTRACT: Neoadjuvant PD-1 blockade may be efficacious in some individuals with high-risk, resectable oral cavity head and neck cancer. To explore correlates of response patterns to neoadjuvant nivolumab treatment and post-surgical recurrences, we analyzed longitudinal tumor and blood samples in a cohort of 12 individuals displaying 33% responsiveness. Pretreatment tumor-based detection of FLT4 mutations and PTEN signature enrichment favors response, and high tumor mutational burden improves recurrence-free survival. In contrast, preexisting and/or acquired mutations (in CDKN2A, YAP1, or JAK2) correlate with innate resistance and/or tumor recurrence. Immunologically, tumor response after therapy entails T cell receptor repertoire diversification in peripheral blood and intratumoral expansion of preexisting T cell clones. A high ratio of regulatory T to T helper 17 cells in pretreatment blood predicts low T cell receptor repertoire diversity in pretreatment blood, a low cytolytic T cell signature in pretreatment tumors, and innate resistance. Our study provides a molecular framework to advance neoadjuvant anti-PD-1 therapy for individuals with resectable head and neck cancer.
Author Info: (1) Division of Dermatology, Department of Medicine, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA
90095, USA (2) Department of Microbiolo
Author Info: (1) Division of Dermatology, Department of Medicine, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA
90095, USA (2) Department of Microbiology and Immunology, Medical University of South Carolina, Charleston, SC 29425, USA (3) Division of Surgical Oncology, Department of Surgery, Winship Cancer Institute, Emory University School of Medicine, Atlanta, GA 30322,
USA (4) Department of Pathology, Medical University of South Carolina, Charleston, SC 29425, USA (5) Division of Pulmonary, Critical Care and Sleep Medicine, Department of Medicine, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA (6) Department of Molecular and Medical Pharmacology, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA (7) Incyte Pharmaceuticals, Wilmington, DE 19803, USA (8) Hollings Cancer Center, Medical University of South Carolina, Charleston, SC 29425, USA (9) Department of Immunology and Microbiology, Medical University of South Carolina, Charleston, SC 29425, USA (10) Department of Otolaryngology – Head and Neck Surgery, Medical University of South Carolina, Charleston, SC 29425, USA (11) Jonsson Comprehensive Cancer Center, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA (12) Department of Cell and Molecular Pharmacology and Experimental Therapeutics, Medical University of South Carolina, Charleston, SC 29425, USA (13) These authors contributed equally (14) Senior author (15)Lead contact.
